Marije R. Benedictus

Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers

IMPORTANCE It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia. OBJECTIVE To determine associations between small-vessel disease and AD pathology. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study from January 2002 to December 2012 using the memory clinic-based Amsterdam Dementia Cohort. The study included 914 consecutive patients with available cerebrospinal fluid (CSF) and magnetic resonance imaging; 547 were patients diagnosed as having AD (54% female, mean [SD], 67 [8]; Mini-Mental State Examination score, mean [SD], 21 [5]), 30 were patients diagnosed as having vascular dementia (37% female, mean [SD], 76 [9]; Mini-Mental State Examination score, mean [SD], 24 [4]), and 337 were control participants with subjective memory complaints (42% female, mean [SD], 59 [59]; Mini-Mental State Examination score, mean [SD], 28 [2]). Linear regressions were performed with CSF biomarkers (log transformed) as dependent variables and magnetic resonance imaging measures (dichotomized) as independent, adjusted for sex, age, mediotemporal lobe atrophy, and diagnosis. An interaction term for diagnosis by magnetic resonance imaging measures was used for estimates per diagnostic group. MAIN OUTCOMES AND MEASURES We examined the associations of magnetic resonance imaging white matter hyperintensities (WMH), lacunes, microbleeds with CSF β-amyloid 42 (Aβ42), total tau, and tau phosphorylated at threonine 181 (P-tau181) as well as for a subset of apolipoprotein E (APOE) ε4 carriers and noncarriers. RESULTS Microbleed presence was associated with lower CSF Aβ42 in AD and vascular dementia (standardized beta = -0.09, P = .003; standardized beta = -0.30, P = .01), and higher CSF tau in controls (standardized beta = 0.10, P = .03). There were no effects for P-tau181. The presence of WMH was associated with lower Aβ42 in control participants and patients with vascular dementia (standardized beta = -0.18, P = .002; standardized beta = -0.32, P = .02) but not in patients with AD. There were no effects for tau or P-tau181. The presence of lacunes was associated with higher Aβ42 in vascular dementia (standardized beta = 0.17, P = .07) and lower tau in AD (standardized beta = -0.07, P = .05) but there were no effects for Aβ42 or P-tau181. Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to ε4 carriers. CONCLUSIONS AND RELEVANCE Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E ε4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.

Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease.

We investigated whether microbleeds and white matter hyperintensities (WMH) in Alzheimers disease (AD) associate more with conventional vascular risk factors or with risk factors that reflect amyloid burden. A total of 371 patients with probable AD were included. WMH (Fazekas 2 or 3) were present in 107 (29%) patients and microbleeds were seen in 98 (26%). Patients with both microbleeds and WMH were older and presented more frequently with lacunes and multiple microbleeds than patients with microbleeds in isolation (all p < 0.05). Using multivariate regression models, we found that WMH presence showed independent associations with age, hypertension, current smoking, and lacune presence. Microbleeds were independently associated with male gender, higher blood pressure, lower cerebrospinal fluid Aβ42, and apolipoprotein E ε4 homozygosity. Separate analyses for microbleeds according to their location showed that these associations were driven by microbleeds in lobar locations. Our results suggest that, unlike WMH, microbleeds in AD are particularly associated with additional amyloid burden, and as such, may relate to cerebral amyloid angiopathy.

Cerebral perfusion in the predementia stages of Alzheimer’s disease

ObjectivesTo investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer’s disease (AD).MethodsData were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-β (Aβ) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex.ResultsDecreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Aβ and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Aβ and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD.ConclusionThe continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression.Key Points• Decreasing CBF relates to more advanced AD stages in all supratentorial regions.• The reduction of CBF does not reach a bottom level.• ASL-CBF has potential as a measure for disease progression in AD.

Microbleeds, Mortality, and Stroke in Alzheimer Disease The MISTRAL Study

IMPORTANCE Microbleeds are more prevalent in patients with Alzheimer disease (AD) compared with the general elderly population. In addition, microbleeds have been found to predict mortality in AD. OBJECTIVE To investigate whether microbleeds in AD increase the risk for mortality, stroke (including intracerebral hemorrhage), and cardiovascular events. DESIGN, SETTING AND PARTICIPANTS The MISTRAL (do MIcrobleeds predict STRoke in ALzheimers disease) Study is a longitudinal cohort study within the memory clinic-based Amsterdam Dementia Cohort. We selected all patients with AD with a baseline visit between January 2, 2002, and December 16, 2009, and microbleeds (n = 111) and matched those (1:2) for age, sex, and magnetic resonance imaging scanner to 222 patients with AD without microbleeds. After a minimal follow-up of 3 years, information on all-cause mortality, stroke-related mortality, and cardiovascular mortality was obtained between November 1, 2012, and May 1, 2014. In addition, we obtained information on the occurrence of incident stroke or transient ischemic attack, cardiovascular events, and nursing home admittance. MAIN OUTCOMES AND MEASURES Stroke-related mortality, incident stroke, and intracerebral hemorrhage. RESULTS Patients had a mean (SD) age of 71.2 (7.8) years and 127 (42%) were female. Compared with having no microbleeds, microbleeds in lobar locations were associated with an increased risk for stroke-related mortality (hazard ratio [HR], 33.9; 95% CI, 2.5-461.7), whereas nonlobar microbleeds were associated with an increased risk for cardiovascular mortality (HR, 12.0; 95% CI, 3.2-44.7). In addition, lobar microbleeds were associated with an increased risk for incident stroke (HR, 3.8; 95% CI, 1.5-10.1) and nonlobar microbleeds with an increased risk for cardiovascular events (HR, 6.2; 95% CI, 1.5-25.0). Even higher risks for incident stroke and cardiovascular events were found in patients using antithrombotic medication. All 5 patients with an intracerebral hemorrhage had lobar microbleeds at baseline; 4 of them used antithrombotics. CONCLUSIONS AND RELEVANCE In patients with AD, the presence of nonlobar microbleeds was associated with an increased risk for cardiovascular events and cardiovascular mortality. Patients with lobar microbleeds had an increased risk for stroke and stroke-related mortality, indicating that these patients should be treated with the utmost care.

White Matter Hyperintensities Relate to Clinical Progression in Subjective Cognitive Decline

Background and Purpose— In patients with subjective cognitive decline, we assessed whether small vessel disease was associated with clinical progression and cognitive decline. Methods— We included 334 patients with subjective cognitive decline. Follow-up was 3±2 years. Results— Fifty-three (16%) patients progressed clinically to mild cognitive impairment or dementia. White matter hyperintensities were associated with clinical progression and with annual decline on memory, attention, executive functioning, and global cognition. Microbleeds and lacunes were not associated with clinical progression or cognitive decline. Conclusions— In patients with subjective cognitive decline, patients with white matter hyperintensities are at increased risk of clinical progression and cognitive decline.

Regional atrophy is associated with impairment in distinct cognitive domains in Alzheimer's disease.

In Alzheimers disease (AD), some patients present with cognitive impairment other than episodic memory disturbances. We evaluated whether occurrence of posterior atrophy (PA) and medial temporal lobe atrophy (MTA) could account for differences in cognitive domains affected.

Quantitative regional validation of the visual rating scale for posterior cortical atrophy

AbstractObjectivesValidate the four-point visual rating scale for posterior cortical atrophy (PCA) on magnetic resonance images (MRI) through quantitative grey matter (GM) volumetry and voxel-based morphometry (VBM) to justify its use in clinical practice.MethodsTwo hundred twenty-nine patients with probable Alzheimer’s disease and 128 with subjective memory complaints underwent 3T MRI. PCA was rated according to the visual rating scale. GM volumes of six posterior structures and the total posterior region were extracted using IBASPM and compared among PCA groups. To determine which anatomical regions contributed most to the visual scores, we used binary logistic regression. VBM compared local GM density among groups.ResultsPatients were categorised according to their PCA scores: PCA-0 (n = 122), PCA-1 (n = 143), PCA-2 (n = 79), and PCA-3 (n = 13). All structures except the posterior cingulate differed significantly among groups. The inferior parietal gyrus volume discriminated the most between rating scale levels. VBM showed that PCA-1 had a lower GM volume than PCA-0 in the parietal region and other brain regions, whereas between PCA-1 and PCA-2/3 GM atrophy was mostly restricted to posterior regions.ConclusionsThe visual PCA rating scale is quantitatively validated and reliably reflects GM atrophy in parietal regions, making it a valuable tool for the daily radiological assessment of dementia.Key Points• Visual rating scale reflects grey matter atrophy in posterior brain regions. • Different PCA scores corresponded well to different quantitative degrees of atrophy. • Inferior parietal gyrus volume influenced assessment based on the visual rating scale. • This simple visual rating scale makes it useful for radiological dementia assessment.

Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease

We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimers disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD).

Thinner temporal and parietal cortex is related to incident clinical progression to dementia in patients with subjective cognitive decline

We aimed to investigate if thinner cortex of the Alzheimers disease (AD)‐signature region was related to clinical progression in patients with subjective cognitive decline (SCD).

White Matter Changes-Related Gait and Executive Function Deficits: Associations with Age and Parkinson's Disease

Background: White matter changes (WMC) are a common finding among older adults and patients with Parkinsons disease (PD), and have been associated with, e.g., gait deficits and executive dysfunction. How the factors age and PD influence WMC-related deficits is, to our best knowledge, not investigated to date. We hypothesized that advanced age and presence of PD leads to WMC-related symptoms while practicing tasks with a low complexity level, and low age and absence of PD leads to WMC-related symptoms while practicing tasks with a high complexity level. Methods: Hundred and thirty-eight participants [65 young persons without PD (50–69 years, yPn), 22 young PD patients (50–69 years, yPD), 36 old persons without PD (70–89 years, oPn) and 15 old PD patients (70–89 years, oPD)] were included. Presence and severity of WMC were determined with the modified Fazekas score. Velocity of walking under single and dual tasking conditions and the Trail Making Test (TMT) were used as gait and executive function parameters. Correlations between presence and severity of WMC, and gait and executive function parameters were tested in yPn, yPD, oPn, and oPD using Spearmans rank correlation, and significance between groups was evaluated with Fishers z-transformed correlation coefficient. Results: yPn and yPD, as well as oPn and oPD did not differ regarding demographic and clinical parameters. Severity of WMC was not significantly different between groups. yPn and yPD displayed significant correlations of WMC with executive function parameters at low levels of task complexity, oPn at intermediate, and oPD at high complexity levels. Conclusion: This study argues for a relevant association of age and PD-related brain pathology with WMC-related gait and executive function deficits.